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The Black Death Alive Once Again?

By Nicole Runkle

Published on February 8, 2012

Rocky Mountain Laboratories, NIAID, NIH

Figure 1: A scanning electron micrograph of Yersinia pestis in the gut of a flea vector

We have all heard of the Black Plague the devastating 14th century epidemic that wiped out 50 million Europeans but what are the chances of this deadly plague returning again to reap its wrath?

History of the Black Plague

From 1347 to 1351, the Black Plague, also known as the Bubonic Plague, is estimated to have killed 30-50% of the European population [1]. First reported in Central Asia in 1339, the plague spread to Africa and was eventually brought over to Europe by Genoese vessels in Marseilles in 1347, wreaking havoc in its wake by killing about 25 million people, including about one-third to one-half of London's population within two years [2, 3, 4]. The Bishop of London even dedicated acres of land in East and West Smithfield for burials due to an overwhelming amount of victims being brought to churchyard cemeteries. At the height of the plague, 200 bodies were buried in these graves each day [3].

Those affected by the plague exhibited very noticeable symptoms. The most conspicuous symptom was the presence of enlarged lymph nodes, which appeared at the time to be tumor growths, in the groin, armpits, and neck; these could become as large as an egg or an apple [5]. Those infected had little chance of survival, and most died within three days of the first symptoms appearing [3].

The bacterium that caused the black plague has been shown to be Yersinia pestis, a Gram-negative bacterium. Some scientists believe in the controversial hypothesis that Y. pestis is also the etiological cause of other pandemics, such as Justinian's plague, which spread from Egypt to the Mediterranean in 541, and the Chinese plague pandemic, which arose in China during the 19th century and spread globally via ship routes passing through Hong Kong [6]. Scientists have been studying the Y. pestis to elucidate the reasons behind this bacterium's devastating effects and to determine if this bacterium was truly the cause of the other pandemics besides the Black Plague.

The Yersinia pestis Bacterium

Before Y. pestis can infect humans, it first infects rodents and fleas. Fleas acquire the bacterium from the blood of infected rodents, and the bacterium subsequently multiplies in the flea's digestive system. When the infected flea bites a human, the flea's bacteria-containing blood passes through that person's open wound, thereby infecting the human.

The black plague propagates through two interconnected cycles: sylvatic and urban. While the sylvatic cycle involves wild animals and does not affect humans, the urban cycle involves spread of the bacterium to domesticated animals and eventually humans. During the sylvatic cycle, a flea bites an infected, wild rodent and serves as a vector by causing the bacterium to spread to other wild rodents, such as prairie dogs, rabbits and mice. Once the flea bites a domesticated animal or human, the urban cycle commences and involves the spread of Y. pestis between domesticated animals or from such animals to humans with the flea still serving as a vector. The bacterium can also spread from human to human through in what is known as the pneumonic plague. While the bubonic plague spreads exclusively through flea vectors, the pneumonic plague can spread through other means, such as when a person breaths in airborne respiratory droplets containing Y. pestis coughed up by an infected person [7, 8, 9].

There are three biovars, or physiologically different strains, of Y. pestis: Antiqua, Medievalis, and Orientalis. These biovars are distinguished based on their ability to ferment glycerol and reduce nitrate [6]. Antiqua, the source of Justinian's plague can ferment glycerol and reduce nitrate. Medievalis, responsible for the Black Death, on the other hand, cannot reduce nitrate. Orientalis, responsible for the third pandemic in China, is unable to ferment glycerol [10]. These characteristics allowed for clear identification of the strains responsible for each pandemic.

Controversy over Y. pestis

In 1894, Alexandre Tersin, a Swiss bacteriologist, identified Y. pestis as the bacterium responsible for causing the Black Death as well as the Justinian and Chinese pandemics. This connection was largely made through historical accounts of symptoms. Despite the historical evidence, many historians and scientists refused to believe that Y. pestis was responsible for the Black Death. Scientists have confirmed that recent smaller plague epidemics were caused by Y. pestis; both historians and scientists believe that these epidemics are mild and less damaging than the 14th century Black Death [3]. For example, in 1995, only 2861 plague cases were reported to the World Health Organization; this number pales in comparison with the millions of people who were affected by the 14th century epidemic [11]. According to scientists, Anthrax or Ebola-like viruses seemed more likely to have caused the Black Plague. Some also argued that fleas, which carried the bacterium to humans, would not have fared the cold temperatures present during the Black Death [3].

Several teams of scientists have been attempting to resolve the controversy over Y. pestis' potential involvement in the Black Death. In 2000, a team led by microbiologist Didier Raoult, M.D., Ph.D. at the University of the Mediterranean in Marseilles, France, extracted DNA from the teeth of two adults and one child exhumed from a 14th century burial site in Montpellier; they used the Polymerase Chain Reaction (PCR) to amplify a specific portion of the extracted genome and identified the sequence as a portion of Y. pestis genome [2]. While some scientists embraced these results, others were skeptical about the validity of this experiment, claiming that the DNA extracted by Raoult's team may have undergone contamination by other DNA samples used in the lab or by the DNA of bacterium related to Y. pestis. Furthermore, many geneticists could not replicate the results, and the same methodology used by Raoult's team failed to work for other ancient DNA extractions, possibly due to degradation of extracted DNA samples by heat and moisture [6].

Laboratory of Molecular Technology/National Cancer Institute

Figure 2: (Click here to view enlarged image.): Next generation sequencing technique.

DNA analysis confirming Y. pestis

The failure to associate Y. pestis with the Black Death with certainty can be attributed to the lack of proper scientific techniques at the time. However, the creation of more advanced molecular techniques has allowed scientists to more recently confirm Y. pestis as the culprit of the Black Death.

In the late 1990's, geneticist Hendrik Poinar tried extracting Y. pestis DNA from teeth and bones of plague victims, but was unsatisfied with the detection tools available based on PCR. He and his colleagues realized that more advanced technology was needed to study and analyze the extracted DNA. Eventually, two groundbreaking technologies emerged: (1) next-generation DNA sequencers and (2) targeted capture. The DNA sequencers could read short snippets of DNA and was perfect for sequencing DNA that had been damaged from spending hundreds of years underground, such as the DNA from plague victims. Targeted capture, which was developed in Germany at about the same time, used lab-synthesized DNA as a template or "bait" to find ancient DNA strands from bone sample. This allowed for more accurate analysis and data since soil-microbes and irrelevant sequences would no longer accidently be identified. This technology was introduced to Poinar through Johannes Krause, a palaeogeneticist from Germany, who co-led the Black Death project alongside Poinar [3].

In 2011, Krause and Poinar used this targeted capture technology to analyze the DNA from 53 bones and 46 teeth from victims buried buried at East Smithfield. Through both new technologies and the sequences from a contemporary Y. pestis strain as "bait," they were able to analyze the DNA from the victims and sequence a short loop of the DNA. They identified this short loop as a Y. pestis plasmid known as pPCP1, which is partially responsible for the plague's ability to infect humans [12]. Their results convinced most scientists that Y. pestis was involved in the Black Death [3]. Krause and Poinar's team were also able to use targeted sequencing to reconstruct a genome of this devastating pathogen [6]. They have found that the strain of Y. pestis that caused the Black Death is no longer in existence but appears to have close emerging relatives today. This ancient variant lies at the base of an evolutionary tree that has branched to 17 contemporary strains of Y. pestis. This shows that the Black Death strain led to the evolution of many forms of Y. pestis that are able to infect humans today. The Black Death strain probably emerged in the fourteenth century, right before its deadly spread across Europe [1, 3, 12].

Y. pestis has changed little over the past 660 years. The genome of the Black Death strain differs from the modern strain only by about 100 nucleotides, and each of these nucleotide substitutions can be found in at least one modern strain. This finding has given rise to the question of what made the Black Death strain so deadly and why modern strains have not produced the same effect today. Scientists currently aim to find what exactly made the Black Death so deadly. Currently, researchers are looking into possibilities such as rearrangements in the genome and environmental and epidemiological factors [3].

Relevance Today

Y. pestis is considered to be the "grandmother" of all plagues today. By analyzing the ancient strain of Y. pestis and comparing it with contemporary strains, scientists can monitor activity of the existing variants, understand current and future outbreaks, and potentially prevent them from having dangerous effects today. For example, sequencing the influenza strain responsible for the 1918 pandemic has helped scientists understand contemporary flu strains.

With the plague still lurking and taking the lives of thousands every year, the complete sequencing of its genome by Poinar and Krause not only gives understanding to the past, but also provides further information about the possibility of its re-emergence. Plague is currently associated with mortality rates of 50-90% when left untreated. Thus, these contemporary strains of Y. pestis still have the potential to cause some damage today. Treatments such as antibiotics and preventative measures such as vaccines that were not available during the 14th century have made plague less destructive in modern times and can lower mortality rates to 15% [11, 13].The chances of the plague causing the same amount of damage as it did during the Black Death over six hundred years ago is extremely unlikely. But on the off chance of its occurrence, scientists are now more adequately prepared and equipped with better understanding than those affected by the plague over 600 years ago.

Works Cited

1. K.I. Bos, V.J. Schuenemann, G.B. Golding, H.A. Burbano, N. Waglechner, B.K. Coombes, J.B. McPhee, S.N. DeWitte, M. Meyer, S. Schmedes, J. Wodd, D.J.D. Earn, D.A. Herring, P. Bauer, H.N. Poinar and J. Krause. (2011, Oct.) "A draft genome of Yersinia pestis from victims of the Black Death". Nature. 478, pp. 506-510.

2. D. Raoult, G. Abourdharam, E. Crubézy, G. Larrouy, B. Ludes, and M. Drancourt. (2000.) "Molecular identification by "suicide PCR" of Yersinia pestis as the agent of Medieval Back Death." Proceedings of the National Academy of Sciences of the United States of America. 97(23), pp. 12800-12803.

3. E. Callaway. (2011, Oct.). "Plague genome: The Black Death decoded." Nature. 478(1), pp. 222-226.

4. National Geographic. "Plague: The Black Death." Available: http://science.nationalgeographic.com/science/health-and-human-body/human-diseases/plague-article/#.

5. A. Schoenstadt. (2006.) "Bubonic Plague Symptoms." MedTV. Available: http://plague.emedtv.com/bubonic-plague/bubonic-plague-symptoms.html.

6. S. Haensch, R. Bianucci, M. Signoli, M. Rajerison, M. Schultz, S. Kacki, M. Vermunt, D. A. Weston, D. Hurst, M. Achtman, E. Carniel, and B. Bramanti. (2010, Oct.). "Distinct Clones of Yersinia pestis Cause the Black Death." PLoS Pathogens. 6(10), e1001134.

7. R.D. Perry and J.D. Fetherston. "Yersinia pestis Etiologic Agent of Plague." Clinical Microbiology Reviews. Vol. 10, pp. 35-66, Jan. 1997.

8. A. Schoenstadt. (2008.) "Pneumonic plague." MedTV. Available: http://plague.emedtv.com/pneumonic-plague/pneumonic-plague.html.

9. B. Tucker. (2010.) "Yersinia pestis." Missouri S&T Microbiology. Available: http://web.mst.edu/~microbio/BIO221_2010/Y_pestis.html.

10. M. Achtman, G. Morelli, P. Zhu, T. Wirth, I. Diehl, B. Kusecek, A.J. Vogler, D.M. Wagner, C.J. Allender, W.R. Easterday, V. Chenal-Francisque, P. Worsham, N.P. Thomson, J. Parkhill, L.E. Lindler, E. Carniel, and P. Keim. (2001, Dec.). "Microevolution and history of the plague bacillus, Yersinia pestis." Proceedings of the National Academy of Sciences of the United States of America. 101(51), pp. 17837-42.

11. Center for Disease Control. (2005.) Plague Fact Sheet. Available: http://www.cdc.gov/ncidod/dvbid/plague/facts.htm.

12. V. Schuenemann, K. Bos, S. DeWitte, S. Schmedes, J. Jamieson, A. Mittnik, S. Forrest, B.K. Coombes, J.W. Wood, D.J.D. Earn, W. White, J. Krause, and H.N. Poinar. (2011.) "Targeted enrichment of ancient pathogens yielding the pPCP1 plasmid of Yersinia pestis from victims of the Black Death." Proceedings of the National Academy of Sciences of the United States of America. 108(38), pp. E746-E752.

13. S.E. Rollins, S.M. Rollins, and E.T. Ryan. (2003.) "Yersinia pestis and the Plague." American Journal of Clinical Pathology. 19(Suppl 1): S78-S85.

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